Phage Display Library Enriched with Long CDR H3 Sequences
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Solution Overview
Problem
Generating functional human antibodies with high specificity and potency for challenging targets such as integral membrane proteins, GPCRs, and viral proteins is resource-intensive and inefficient due to the need for extensive screening in conventional phage display libraries, which often have limited representation of longer CDR H3 sequences.
Innovation Solution
A phage display library is created with a high proportion of human scFv antibodies featuring variable heavy chain CDR H3 sequences of 18 to 24 amino acids in length, generated from a human germline sequence, to enhance specificity and potency for challenging targets.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional phage display libraries are used to generate human antibodies, then the screening process can identify antibodies with appropriate functionality, but the process requires extensive screening of tens of thousands of antibodies and represents significant investment of time and resources
Solution Approach 1:
The patent applies local quality by specifically enriching the CDR H3 region of the antibody library with longer sequences (18-30 amino acids) while maintaining other regions at conventional lengths. This targeted modification of a specific local region (CDR H3) increases the probability of finding functional antibodies against challenging targets without requiring extensive screening of the entire library, thus resolving the contradiction between reliability and time loss.
Solution Approach 2:
The patent changes the parameter of CDR H3 length from conventional (10-15 amino acids) to extended (18-30 amino acids) in the phage display library. This parameter change in the CDR H3 region specifically improves the ability to bind challenging targets such as integral membrane proteins and viral proteins, reducing the need for extensive screening while maintaining high functionality rates.
2Reliability
If conventional phage display libraries with typical CDR H3 lengths are used, then the library construction is straightforward, but the likelihood of obtaining antibodies with high specificity and potency for challenging targets is low
Solution Approach 1:
The patent applies local quality by specifically modifying the CDR H3 region length while keeping other antibody regions conventional. This targeted approach improves specificity and potency for challenging targets without requiring complete redesign of the entire antibody structure or library construction process, thus managing complexity while enhancing performance.
Solution Approach 2:
The patent applies preliminary action by pre-enriching the library with antibodies having extended CDR H3 sequences (18-30 amino acids) before screening. This preliminary modification of the library composition increases the probability of finding functional antibodies against challenging targets from the outset, reducing the need for extensive screening and iterative optimization.
3Reliability
If the CDR H3 length is extended to 18-30 amino acids, then the probability of obtaining functional antibodies against challenging targets increases, but the library requires specialized construction methods
Solution Approach 1:
The patent changes the CDR H3 length parameter to 18-30 amino acids, which increases functional antibody yield against challenging targets. The patent describes specific construction methods including PCR amplification with primers designed for extended CDR H3 regions and cloning into phage display vectors, providing a systematic approach that maintains ease of manufacture despite the parameter change.
Data Source
AI summary
The present invention relates to a library (in particular a phage display library) from which an improved human antibody having greater specificity and potency for its target may be generated; and to methods of generating such a human antibody. In particular, the invention relates to a human antibodies against challenging targets obtainable from such a library and which have HCDR3s of at least 18 amino acids in length.